Study Rationale: Alpha-synuclein is the key protein involved in Parkinson’s disease (PD). In the process of the disease, it loses its proper shape and clumps together. These clumps are toxic to cells in the brain and cause the symptoms associated with PD. This protein can have different forms due to modifications that are attached to the protein, so called post-translational modifications (PTMs). These PTMs can have functional (positive) and detrimental (negative) effects on how the protein interacts within the cellular environment. It is of key interest to know which PTMs are involved in PD and how these might drive the progression of the disease.
Hypothesis: With this project we aim to map the distribution of PTMs across the brain to determine whether particular PTMs are involved in the disease progression.
Study Design: The main method used for this project is mass spectrometry-based proteomics. Mass spectrometers are machines that analyze the weight of material and proteomics describes the discipline investigating the protein composition of cells. PTMs change the weight of proteins and by analyzing the weight distribution of the proteins that are found in a cell we can, with the help of computational methods, establish what modifications are present on proteins. We developed a method called Deep Visual Proteomics which allows us to combine these methods with microscopy images. We can look directly at images of brain tissue and then analyze the proteomes of areas that we can select either manually or automatically according to certain criteria. With this approach we can accurately map PTMs to specific areas in the brain.
Impact on Diagnosis/Treatment of Parkinson’s disease: PTMs affect how proteins behave. By discovering which PTMs are present in PD we can better understand why alpha-synuclein behaves the way it does. This knowledge in turn can aid in establishing how PD develops which might lead to new approaches to treat it.
Next Steps for Development: If we find specific PTMs that are directly connected to the development of PD, we can use these as targets for new drugs to treat PD or potentially as biomarkers to discover if a person is suffering from the disease before symptoms develop.